Faster onset of effect and greater efficacy of NN1731 compared with rFVIIa, aPCC and FVIII in tail bleeding in hemophilic mice

Holmberg, Heidi L.; Lauritzen, Brian; Tranholm, Mikael; Ezban, Mirella

doi:10.1111/j.1538-7836.2009.03532.x

Cited by 38 publications

(47 citation statements)

References 26 publications

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“…These include FVIIa with a prolonged half-life [38][39][40][41][42] and increased activity, [43][44][45] activated FX mutations, 46 and FX variants that can be activated directly by thrombin. 47 We believe that FIX variants could have several advantages compared with these approaches.…”

Section: Fviii-bypassing Agents Formentioning

confidence: 99%

Engineered factor IX variants bypass FVIII and correct hemophilia A phenotype in mice

Milanov

Ivanciu

Abriss

et al. 2012

Blood

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The complex of the serine protease factor IX (FIX) and its cofactor, factor VIII (FVIII), is crucial for propagation of the intrinsic coagulation cascade. Absence of either factor leads to hemophilia, a disabling disorder marked by excessive hemorrhage after minor trauma. FVIII is the more commonly affected protein, either by X-chromosomal gene mutations or in autoimmune-mediated acquired hemophilia. Whereas substitution of FVIII is the mainstay of hemophilia A therapy, treatment of patients with inhibitory Abs remains challenging. In the present study, we report the development of FIX variants that can propagate the intrinsic coagulation cascade in the absence of FVIII. FIX variants were expressed in FVIII-knockout (FVIII-KO) mice using a nonviral genetransfer system. Expression of the variants shortened clotting times, reduced blood loss after tail-clip assay, and reinstalled clot formation, as tested by in vivo imaging of laser-induced vessel injury. In IntroductionThe intrinsic coagulation cascade is a tightly regulated proteaseand cofactor-dependent amplification system that ensures the formation of stable clots after injury. 1 Within this system, deficiencies of the coagulation cofactor, factor VIII (FVIII), or the corresponding coagulation protease, factor IX (FIX), lead to the X-chromosomal inherited bleeding disorders hemophilia A and hemophilia B, respectively. Hemophilia A occurs approximately in 1 of 5000 newborn boys, whereas hemophilia B is less common. 2 Untreated, hemophilia presents with spontaneous bleeding preferentially into large joints and skeletal muscle, and internal and intracranial bleedings can also occur. Substitution of deficient coagulation factors by intravenous infusion of plasma-derived or recombinant coagulation factor concentrates is the therapy of choice. In the last decades, treatment has evolved from so-called on-demand treatment for acute injury/hemorrhage to a secondary preventative approach with regular prophylactic infusions. Prophylactic treatment, securing plasma levels above 1% of normal, already prevents the major long-term consequences of the disease: joint damage and muscular atrophy. 3,4 A major obstacle for protein substitution therapy is the occurrence of neutralizing Abs directed against the FVIII protein. This can either be a result of an immune response after exogenous protein exposure 5 or may appear in adult patients as a spontaneous auto-immune event. 6 In these cases, FVIII infusion is often ineffective and so-called bypassing agents are used. These agents consist of constitutively activated proteases such as activated factor VII (FVIIa), and promote clot formation directly without restoring the intrinsic amplification loop. Although these therapeutics are efficient at stopping acute bleeding, limitations include the relatively short half-lives of activated proteases in the circulation and potential vascular risks in long-term treatment. 7,8 In the present study, we report on the generation of FIX variants with FVIII-independent clotting activity that we...

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Section: Fviii-bypassing Agents Formentioning

confidence: 99%

Engineered factor IX variants bypass FVIII and correct hemophilia A phenotype in mice

Milanov

Ivanciu

Abriss

et al. 2012

Blood

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“…8 Because ICH in patients on warfarin is related to a bigger hematoma size and a worse prognosis, the primary aim of acute oral anticoagulant ICH management is to reverse the anticoagulatory effect of vitamin K antagonists. 9 In addition to the replacement of coagulation factors such as prothrombin complex concentrate 10 (PCC) and fresh-frozen plasma 10 (FFP), the administration of hemostatic agents such as recombinant Factor VII activated 11 (FVIIa), and tranexamic acid 12 (TA) may be beneficial. Unfortunately, clinical and experimental studies comparing these regimens in W-ICH do not exist to date.…”

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confidence: 99%

Comparative Effectiveness of Hemostatic Therapy in Experimental Warfarin-Associated Intracerebral Hemorrhage

Illanes

Zhou

Schwarting

et al. 2011

Stroke

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Background and Purpose— Intracerebral hemorrhage associated with oral anticoagulants has a poor prognosis. Current treatment guidelines are based on case series and plausibility only, and a common consensus on effective hemostatic therapy is missing. We compared the effectiveness of diverse hemostatic approaches in a mouse model of warfarin-associated intracerebral hemorrhage. Methods— Male C57BL/6 mice received anticoagulant treatment with warfarin (0.4 mg/kg for 3 days). Intracerebral hemorrhage was induced by striatal injection of collagenase, and 30 minutes later, mice received an intravenous injection of saline (200 μL n=15), prothrombin complex concentrate (100 U/kg, n=10), fresh-frozen plasma (200 μL, n=13), recombinant human Factor VII activated (3.5 mg/kg, n=8 and 10 mg/kg, n=8), or tranhexamic acid (400 mg/kg, n=12). Intracerebral hemorrhage volume was quantified on T2-weighted images after 24 hours. Results— Mean hematoma volumes were 7.4±1.8 mm 3 in the nonwarfarin controls and 21.9±5.0 mm 3 in the warfarin group receiving saline. Prothrombin complex concentrate (7.5±2.3 mm 3 ) and fresh-frozen plasma (8.7±2.1) treatment resulted in significantly smaller hematoma volume compared with saline. Recombinant human Factor VII activated (10 mg/kg: 14.7±3.4; 3.5 mg/kg: 15.0±6.8 mm 3 ) and tranexamic acid (16.2±4.1 mm 3 ) were less effective. Water content in the hemorrhagic hemisphere was similar in all groups except for tranexamic acid in which it was significantly increased. Conclusions— Prothrombin complex concentrate and fresh-frozen plasma effectively prevent hematoma growth in murine warfarin-associated intracerebral hemorrhage, whereas Factor VIIa was less effective. Tranexamic acid exacerbates perihematoma edema in this mouse warfarin-associated intracerebral hemorrhage model.

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“…It has demonstrated increased thrombin generation on preactivated platelets in a cell-based model resulting in the formation of a stable fibrin clot with tighter fibrin structure [8,20]. Accordingly, it also has been shown to have increased hemostatic properties in animal models [11,21].…”

Section: Discussionmentioning

confidence: 99%

“…A novel analogue of rFVIIa (vatreptacog alfa) with a substitution of three amino acids at positions 158, 296 and 298 (V158D/ E296V/M298Q) has increased tissue factor (TF)-independent FXa generation activity on the platelet surface, whereas the TF-dependent FX activation is similar to that of rFVIIa [7,8]. Vatreptacog alfa has shown improved thrombin generation and clotting in whole blood from hemophilia patients [9,10] and factor VIII-deficient mice [11]. Vatreptacog alfa has completed phase II trials and has shown good efficacy and no safety concerns at doses up to 80 mg/kg [12].…”

Section: Introductionmentioning

confidence: 99%

Overcoming delayed in-vitro response to rFVIIa

Brophy

Martin²,

Barrett³

et al. 2011

Blood Coagulation &Amp; Fibrinolysis

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In a previous pharmacokinetic/pharmacodynamic study in nonbleeding hemophilia patients, variability in laboratory response to recombinant factor VIIa (rFVIIa) 90 μg/kg was noted, and the patients were described as delayed or rapid laboratory responders based on time to clot formation. The current study determined whether in-vitro experiments could reproduce previous in-vivo findings; whether the delayed laboratory response to rFVIIa 90 μg/kg is improved by spiking with high-dose rFVIIa or rFVIIa analogue (vatreptacog alfa); whether a dose-response is observed with our method. In-vitro experiments were conducted in our previous patient cohort using rFVIIa 1.28 and 3.84 μg/ml and vatreptacog alfa 0.28 and 0.56 μg/ml. Whole blood studies were conducted using the Hemodyne Hemostasis Analysis System (platelet contractile force, clot elastic modulus, force onset time) and rotational thromboelastometry (clotting time, maximum clot firmness). Spiking with rFVIIa 1.28 μg/ml showed the same distribution of delayed and rapid laboratory response as observed previously. Increasing in-vitro rFVIIa concentrations improved the coagulation parameters; however, there remained delayed and rapid responders. Vatreptacog alfa improved the coagulation parameters at all concentrations tested, and the 0.56 μg/ml concentration normalized the force onset time, platelet contractile force, clot elastic modulus and clotting time parameters. A dose-response was observed with both assays. There was good agreement between the laboratory responses obtained after intravenous administration of rFVIIa 90 μg/kg and in-vitro spiking studies. Escalating rFVIIa and vatreptacog alfa concentrations improved coagulation parameters in all patients compared to rFVIIa 1.28 μg/ml. Vatreptacog alfa produced more pronounced coagulation effects at lower concentrations than rFVIIa; and the 0.56 μg/ml concentration completely normalized responses in all patients.

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Faster onset of effect and greater efficacy of NN1731 compared with rFVIIa, aPCC and FVIII in tail bleeding in hemophilic mice

Abstract: This study shows that NN1731 has a greater efficacy and faster resolution of bleeding in a severe bleeding model in hemophilia A mice compared with any of the other agents tested.

Cited by 38 publications

References 26 publications

Engineered factor IX variants bypass FVIII and correct hemophilia A phenotype in mice

Engineered factor IX variants bypass FVIII and correct hemophilia A phenotype in mice

Comparative Effectiveness of Hemostatic Therapy in Experimental Warfarin-Associated Intracerebral Hemorrhage

Overcoming delayed in-vitro response to rFVIIa

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